Mandelic hydrazides

ABSTRACT

Novel mandelic hydrazides of the formula (I), in which R 1 -R 11  have the meanings indicated in claim 1, are SGK inhibitors and can be used for the treatment of SGK-induced diseases and complaints, such as diabetes, obesity, metabolic syndrome (dyslipidaemia), systemic and pulmonary hypertonia, cardiovascular diseases and kidney diseases, generally in fibroses and inflammatory processes of any type.

BACKGROUND OF THE INVENTION

The invention was based on the object of finding novel compounds havingvaluable properties, in particular those which can be used for thepreparation of medicaments.

The present invention relates to compounds in which the inhibition,regulation and/or modulation of signal transduction of kinases, inparticular cell volume-regulated human kinase h-sgk (human serum andglucocorticoid dependent kinase or SGK), plays a role, furthermore topharmaceutical compositions which comprise these compounds, and to theuse of the compounds for the treatment of SGK-induced diseases.

The SGKs with the isoforms SGK-1, SGK-2 and SGK-3 are a serine/threonineprotein kinase family (WO 02/17893).

The compounds according to the invention are preferably selectiveinhibitors of SGK-1. They may furthermore be inhibitors of SGK-2 and/orSGK-3.

In detail, the present invention thus relates to compounds whichinhibit, regulate and/or modulate SGK signal transduction, tocompositions which comprise these compounds, and to processes for theuse thereof for the treatment of SGK-induced diseases and complaints,such as diabetes (for example diabetes mellitus, diabetic nephropathy,diabetic neuropathy, diabetic angiopathy and microangiopathy), obesity,metabolic syndrome (dyslipidaemia), systemic and pulmonary hypertonia,cardiovascular diseases (for example cardiac fibroses after myocardialinfarction, cardiac hypertrophy and cardiac insufficiency,arteriosclerosis) and kidney diseases (for example glomerulosclerosis,nephrosclerosis, nephritis, nephropathy, electrolyte excretiondisorder), generally in fibroses and inflammatory processes of any type(for example liver cirrhosis, pulmonary fibrosis, fibrosingpancreatitis, rheumatism and arthroses, Crohn's disease, chronicbronchitis, radiation fibrosis, sclerodermatitis, cystic fibrosis,scarring, Alzheimer's disease).

The compounds according to the invention can also inhibit the growth oftumour cells and tumour metastases and are therefore suitable for tumourtherapy.

The compounds according to the invention are also used in the treatmentof peptic ulcers, in particular in the case of forms triggered bystress.

The compounds according to the invention are furthermore used for thetreatment of coagulopathies, such as, for example, dysfibrinogenaemia,hypoproconvertinaemia, haemophilia B, Stuart-Prower defect, prothrombincomplex deficiency, consumption coagulopathy, hyperfibrinolysis,immunocoagulopathy or complex coagulopathies, and also in neuronalexcitability, for example epilepsy. The compounds according to theinvention can also be employed therapeutically in the treatment ofglaucoma or a cataract. The compounds according to the invention arefurthermore used in the treatment of bacterial infections and inantiinfection therapy. The compounds according to the invention can alsobe employed therapeutically for increasing learning ability andattention. In addition, the compounds according to the invention countercell ageing and stress and thus increase life expectancy and fitness inthe elderly.

The compounds according to the invention are furthermore used in thetreatment of tinnitus.

The identification of small compounds which specifically inhibit,regulate and/or modulate SGK signal transduction is therefore desirableand an aim of the present invention.

It has been found that the compounds according to the invention andsalts thereof have very valuable pharmacological properties while beingwell tolerated.

In particular, they exhibit SGK-inhibiting properties.

The present invention therefore relates to compounds according to theinvention as medicaments and/or medicament active ingredients in thetreatment and/or prophylaxis of the said diseases and to the use ofcompounds according to the invention for the preparation of apharmaceutical for the treatment and/or prophylaxis of the said diseasesand also to a process for the treatment of the said diseases whichcomprises the administration of one or more compounds according to theinvention to a patient in need of such an administration.

The host or patient may belong to any mammal species, for example aprimate species, particularly humans; rodents, including mice, rats andhamsters; rabbits; horses, cows, dogs, cats, etc. Animal models are ofinterest for experimental investigations, where they provide a model forthe treatment of a human disease.

For identification of a signal transduction pathway and for detection ofinteractions between various signal transduction pathways, variousscientists have developed suitable models or model systems, for examplecell culture models (for example Khwaja et al., EMBO, 1997, 16, 2783-93)and models of transgenic animals (for example White et al., Oncogene,2001, 20, 7064-7072). For the determination of certain stages in thesignal transduction cascade, interacting compounds can be utilised inorder to modulate the signal (for example Stephens et al., BiochemicalJ., 2000, 351, 95-105). The compounds according to the invention canalso be used as reagents for testing kinase-dependent signaltransduction pathways in animals and/or cell culture models or in theclinical diseases mentioned in this application.

Measurement of the kinase activity is a technique which is well known tothe person skilled in the art. Generic test systems for thedetermination of the kinase activity using substrates, for examplehistone (for example Alessi et al., FEBS Lett. 1996, 399, 3, pages333-338) or the basic myelin protein, are described in the literature(for example Campos-González, R. and Glenney, Jr., J. R. 1992, J. Biol.Chem. 267, page 14535).

Various assay systems are available for identification of kinaseinhibitors. In the scintillation proximity assay (Sorg et al., J. of.Biomolecular Screening, 2002, 7, 11-19) and the flashplate assay, theradioactive phosphorylation of a protein or peptide as substrate ismeasured using γATP. In the presence of an inhibitory compound, areduced radioactive signal, or none at all, can be detected.Furthermore, homogeneous time-resolved fluorescence resonance energytransfer (HTR-FRET) and fluorescence polarisation (FP) technologies areuseful as assay methods (Sills et al., J. of Biomolecular Screening,2002, 191-214).

Other non-radioactive ELISA assay methods use specificphospho-anti-bodies (phospho-ABs). The phospho-AB only binds thephosphorylated substrate. This binding can be detected bychemoluminescence using a second peroxidase-conjugated antisheepantibody (Ross et al., Biochem. J., 2002, 366, 977-981).

PRIOR ART

WO 00/62781 describes the use of medicaments comprising inhibitors ofcell volume-regulated human kinase H-SGK.

Acylhydrazones are described as SGK inhibitors in WO 2005037773. Otheracylmandelic hydrazides are described as fungicides in WO 96/17840 andby P. Legrel in Tetrahedron 1988, 44, 4805-4814.Benzylidenebenzohydrazides having an antibacterial action are describedin WO 02/070464 A2. The use of acylhydrazides for the treatment ofbacterial infections is disclosed in WO 01/70213.

Other acylhydrazone derivatives, inter alia for the treatment ofdiabetes complications, are disclosed in JP 11-106371.

Methoxy-substituted aromatic acylhydrazone derivatives for the treatmentof cancer are described by T. Kametani et al. in Yakugaku Zasshi (1963),83, 851-855 and in Yakugaku Zasshi (1963), 83, 844-847.

Other aromatic acylhydrazone derivatives as sedative enhancers and forlowering blood pressure are disclosed in JP 41-20699.

The use of kinase inhibitors in antiinfection therapy is described by C.Doerig in Cell. Mol. Biol. Lett. Vol. 8, No. 2A, 2003, 524-525.

The use of kinase inhibitors in obesity is described by N. Perrotti inJ. Biol. Chem. 2001, Mar. 23; 276(12):9406-9412.

The following references suggest and/or describe the use of SGKinhibitors in disease treatment:

-   1: Chung E J, Sung Y K, Farooq M, Kim Y, Im S, Tak W Y, Hwang Y J,    Kim Y I, Han H S, Kim J C, Kim M K. Gene expression profile analysis    in human hepatocellular carcinoma by cDNA microarray. Mol. Cells.    2002; 14:382-7.-   2: Brickley D R, Mikosz C A, Hagan C R, Conzen S D. Ubiquitin    modification of serum and glucocorticoid-induced protein kinase-1    (SGK-1). J Biol. Chem. 2002; 277:43064-70.-   3: Fillon S, Klingel K, Warntges S, Sauter M, Gabrysch S, Pestel S,    Tanneur V, Waldegger S, Zipfel A, Viebahn R, Haussinger D, Broer S,    Kandolf R, Lang F. Expression of the serine/threonine kinase hSGK1    in chronic viral hepatitis. Cell Physiol Biochem. 2002; 12:47-54.-   4: Brunet A, Park J, Tran H, Hu L S, Hemmings B A, Greenberg M E.    Protein kinase SGK mediates survival signals by phosphorylating the    forkhead transcription factor FKHRL1 (FOXO3a). Mol Cell Biol 2001;    21:952-65-   5: Mikosz C A, Brickley D R, Sharkey M S, Moran T W, Conzen S D.    Glucocorticoid receptor-mediated protection from apoptosis is    associated with induction of the serine/threonine survival kinase    gene, sgk-1. J Biol. Chem. 2001; 276:16649-54.-   6: Zuo Z, Urban G, Scammell J G, Dean N M, McLean T K, Aragon I,    Honkanen R E. Ser/Thr protein phosphatase type 5 (PP5) is a negative    regulator of glucocorticoid receptor-mediated growth arrest.    Biochemistry. 1999; 38:8849-57.-   7: Buse P, Tran S H, Luther E, Phu P T, Aponte G W, Firestone G L.    Cell cycle and hormonal control of nuclear-cytoplasmic localisation    of the serum- and glucocorticoid-inducible protein kinase, Sgk, in    mammary tumour cells. A novel convergence point of    anti-proliferative and proliferative cell signalling pathways. J    Biol. Chem. 1999; 274:7253-63.-   8: M. Hertweck, C. Gobel, R. Baumeister: C. elegans SGK-1 is the    critical component in the Akt/PKB Kinase complex to control stress    response and life span. Developmental Cell, Vol. 6, 577-588, April,    2004.

SUMMARY OF THE INVENTION

The invention relates to compounds of the formula I

in which

-   R¹, R² each, independently of one another, denote H, CHO or acetyl,-   R³, R⁴, R⁵, R⁶, R⁷,-   R⁸, R⁹, R¹⁰, R¹¹ each, independently of one another, denote H, A,    OSO₂A, Hal, NO₂, OR¹², N(R¹²)₂, CN, O—COA, —[C(R¹²)₂]_(n)COOR¹²,    O—[C(R¹²)₂]_(n)COOR¹², SO₃H, —[C(R¹²)₂]_(n)Ar, —CO—Ar,    O—[C(R¹²)₂]_(n)Ar, —[C(R¹²)₂]_(n)Het, —[C(R¹²)₂]_(n)C≡CH,    O—[C(R¹²)₂]_(n)C≡CH, —[C(R¹²)₂]_(n)CON(R¹²)₂,    —[C(R¹²)₂]_(n)CONR¹²N(R¹²)₂, O—[C(R¹²)₂]_(n)CON(R¹²)₂,    O—[C(R¹²)₂]OCONR¹²N(R¹²)₂, NR¹²COA, NR¹²CON(R¹²)₂, NR¹²SO₂A,    N(SO₂A)₂, COR¹², S(O)_(m)Ar, SO₂NR¹² or S(O)_(m)A,-   R³ and R⁴ together also denote CH═CH—CH═CH,-   R³ and R⁴, R⁷ and R⁸-   or R⁸ and R⁹ together also denote alkylene having 3, 4 or 5 C atoms,    in which one or two CH₂ groups may be replaced by oxygen,-   A denotes unbranched or branched alkyl having 1-6 C atoms, in which    1-7H atoms may be replaced by F, or cyclic alkyl having 3-7 C atoms,-   Ar denotes phenyl, naphthyl or biphenyl, each of which is    unsubstituted or mono-, di- or trisubstituted by Hal, A, OR¹²,    N(R¹²)₂, NO₂, CN, phenyl, CON(R¹²)₂, NR¹²COA, NR¹²CON(R¹²)₂,    NR¹²SO₂A, COR¹², SO₂N(R¹²)₂, S(O)_(m)A, —[C(R¹²)₂]_(n)—COOR¹² and/or    —O[C(R¹²)₂]_(n)—COOR¹²-   Het denotes a mono- or bicyclic saturated, unsaturated or aromatic    heterocycle having 1 to 4 N, O and/or S atoms, which may be mono-,    di- or trisubstituted by Hal, A, OR¹², N(R¹²)₂, NO₂, CN, COOR¹²,    CON(R¹²)₂, NR¹²COA, NR¹²SO₂A, COR¹², SO₂NR¹², S(O)_(m)A, ═S, ═NR¹²    and/or ═O (carbonyl oxygen),-   R¹² denotes H or A,-   Hal denotes F, Cl, Br or I,-   m denotes 0, 1 or 2,-   n denotes 0, 1, 2 or 3,-   o denotes 1, 2 or 3,    and pharmaceutically usable derivatives, salts, solvates and    stereoisomers thereof, including mixtures thereof in all ratios.

The invention relates to the compounds of the formula I and saltsthereof and to a process for the preparation of compounds of the formulaI according to claims 1-16 and pharmaceutically usable derivatives,solvates, salts and stereoisomers thereof, characterised in that

-   a) a compound of the formula II

-   -   in which    -   R¹, R⁷, R⁸, R⁹, R¹⁰ and R¹¹ have the meanings indicated in claim        1,        is reacted with a compound of the formula III

-   -   in which    -   L denotes Cl, Br, I or a free or reactively functionally        modified OH group, and    -   R², R³, R⁴, R⁵ and R⁶ have the meanings indicated in claim 1,        or

-   b) a compound of the formula IV

-   -   in which    -   R², R³, R⁴, R⁵ and R⁶ have the meanings indicated in claim 1,        is reacted with a compound of the formula V

-   -   in which    -   L denotes Cl, Br, I or a free or reactively functionally        modified OH group, and    -   R¹, R⁷, R⁸, R⁹, R¹⁰ and R¹¹ have the meanings indicated in claim        1,        or

-   c) a radical R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰ and/or R¹¹ in a    compound of the formula I is converted into another radical R¹, R²,    R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰ and/or R¹¹    by cleaving an ether by hydrolysis or hydrogenolysis,    and/or a base or acid of the formula I is converted into one of its    salts.

The invention also relates to the stereoisomers (E, Z isomers) and thehydrates and solvates of these compounds. Solvates of the compounds aretaken to mean adductions of inert solvent molecules onto the compoundswhich form owing to their mutual attractive force. Solvates are, forexample, mono- or dihydrates or alcoholates.

Pharmaceutically usable derivatives are taken to mean, for example, thesalts of the compounds according to the invention and also so-calledprodrug compounds.

Prodrug derivatives are taken to mean compounds of the formula I whichhave been modified with, for example, alkyl or acyl groups, sugars oroligopeptides and which are rapidly cleaved in the organism to form theactive compounds according to the invention.

These also include biodegradable polymer derivatives of the compoundsaccording to the invention, as is described, for example, in Int. J.Pharm. 115, 61-67 (1995).

The expression “effective amount” means the amount of a medicament orpharmaceutical active ingredient which causes a biological or medicalresponse which is sought or aimed at, for example by a researcher orphysician, in a tissue, system, animal or human.

In addition, the expression “therapeutically effective amount” means anamount which, compared with a corresponding subject who has not receivedthis amount, has the following consequence:

improved treatment, healing, prevention or elimination of a disease,syndrome, condition, complaint, disorder or side effects or also thereduction in the progress of a disease, complaint or disorder.

The expression “therapeutically effective amount” also encompasses theamounts which are effective for increasing normal physiologicalfunction.

The invention also relates to mixtures of the compounds of the formula Iaccording to the invention, for example mixtures of two diastereomers orenantiomers, for example in the ratio 1:1, 1:2, 1:3, 1:4, 1:5, 1:10,1:100 or 1:1000.

These are particularly preferably mixtures of stereoisomeric compounds,in particular the compounds according to the invention are in the formof the racemate.

For all radicals which occur more than once, their meanings areindependent of one another.

Above and below, the radicals and parameters R¹, R², R³, R⁴, R⁵, R⁶, R⁷,R⁸, R⁹, R¹⁰ and R¹¹ have the meanings indicated for the formula I,unless expressly indicated otherwise.

A denotes alkyl, is unbranched (linear) or branched, and has 1, 2, 3, 4,5 or 6 C atoms. A preferably denotes methyl, furthermore ethyl, propyl,isopropyl, butyl, isobutyl, sec-butyl or tert-butyl, furthermore alsopentyl, 1-, 2- or 3-methylbutyl, 1,1-, 1,2- or 2,2-dimethylpropyl,1-ethylpropyl, hexyl, 1-, 2-, 3- or 4-methylpentyl, 1,1-, 1,2-, 1,3-,2,2-, 2,3- or 3,3-dimethylbutyl, 1- or 2-ethylbutyl,1-ethyl-1-methylpropyl, 1-ethyl-2-methylpropyl, 1,1,2- or1,2,2-trimethylpropyl, further preferably, for example, trifluoromethyl.A very particularly preferably denotes alkyl having 1, 2, 3, 4, 5 or 6 Catoms, preferably methyl, ethyl, propyl, isopropyl, butyl, isobutyl,sec-butyl, tert-butyl, pentyl, hexyl, trifluoromethyl, pentafluoroethylor 1,1,1-trifluoroethyl.

Ac denotes acetyl, Bn denotes benzyl, Ms denotes —SO₂CH₃.

R¹ preferably denotes H, CHO or acetyl, particularly preferably H.

R² preferably denotes H.

R³R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹ preferably denote, each independentlyof one another, H, A, Hal, OR¹² or O—[C(R¹²)₂]_(n)Ar.

R³ particularly preferably denotes H, A or Hal.

R⁶ particularly preferably denotes OH.

R⁸ particularly preferably denotes OH, A, phenoxy or Hal.

R⁴, R⁵, R⁷, R⁹, R¹⁰, R¹¹ particularly preferably denote H or A.

R⁷, R¹⁰, R¹¹ also particularly preferably denote, each independently ofone another, H or Hal.

R¹² particularly preferably denotes H.

Ar denotes, for example, phenyl, o-, m- or p-tolyl, o-, m- orp-ethylphenyl, o-, m- or p-propylphenyl, o-, m- or p-isopropylphenyl,o-, m- or p-tert-butylphenyl, o-, m- or p-hydroxyphenyl, o-, m- orp-nitrophenyl, o-, m- or paminophenyl, o-, m- orp-(N-methylamino)phenyl, o-, m- or p-(N-methylaminocarbonyl)phenyl, o-,m- or p-acetamidophenyl, o-, m- or p-methoxyphenyl, o-, m- orp-ethoxyphenyl, o-, m- or p-ethoxycarbonylphenyl, o-, m- orp-(N,N-dimethylamino)phenyl, o-, m- orp-(N,N-dimethylaminocarbonyl)phenyl, o-, m- or p-(N-ethylamino)phenyl,o-, m- or p-(N,N-diethylamino)phenyl, o-, m- or p-fluorophenyl, o-, m-or p-bromophenyl, o-, m- or pchlorophenyl, o-, m- orp-(methylsulfonamido)phenyl, o-, m- or p-(methylsulfonyl)phenyl, o-, m-or p-cyanophenyl, o-, m- or p-ureidophenyl, o-, m- or p-formylphenyl,o-, m- or p-acetylphenyl, o-, m- or p-aminosulfonylphenyl, o-, m- orp-carboxyphenyl, o-, m- or p-carboxymethylphenyl, o-, m- orp-carboxymethoxyphenyl, further preferably 2,3-, 2,4-, 2,5-, 2,6-, 3,4-or 3,5-difluorophenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or3,5-dichlorophenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-dibromophenyl,2,4- or 2,5-dinitrophenyl, 2,5- or 3,4-dimethoxyphenyl,3-nitro-4-chlorophenyl, 3-amino-4-chloro-, 2-amino-3-chloro-,2-amino-4-chloro-, 2-amino-5-chloro- or 2-amino-6-chlorophenyl,2-nitro-4-N,N-dimethylamino- or 3-nitro-4-N,N-dimethylaminophenyl,2,3-diaminophenyl, 2,3,4-, 2,3,5-, 2,3,6-, 2,4,6- or3,4,5-trichlorophenyl, 2,4,6-trimethoxyphenyl,2-hydroxy-3,5-dichlorophenyl, p-iodophenyl, 3,6-dichloro-4-aminophenyl,4-fluoro-3-chlorophenyl, 2-fluoro-4-bromophenyl,2,5-difluoro-4-bromophenyl, 3-bromo-6-methoxyphenyl,3-chloro-6-methoxyphenyl, 3-chloro-4-acetamidophenyl,3-fluoro-4-methoxyphenyl, 3-amino-6-methylphenyl,3-chloro-4-acetamidophenyl or 2,5-dimethyl-4-chlorophenyl.

Ar preferably denotes, for example, phenyl which is unsubstituted ormono-, di- or trisubstituted by Hal, A, OR¹⁰, SO₂A, COOR¹⁰ or CN, veryparticularly preferably phenyl which is unsubstituted or mono-, di- ortrisubstituted by Hal and/or A, in particular Ar denotes phenyl.

Irrespective of further substitutions, Het denotes, for example, 2- or3-furyl, 2- or 3-thienyl, 1-, 2- or 3-pyrrolyl, 1-, 2-, 4- or5-imidazolyl, 1-, 3-, 4- or 5-pyrazolyl, 2-, 4- or 5-oxazolyl, 3-, 4- or5-isoxazolyl, 2-, 4- or 5-thiazolyl, 3-, 4- or 5-isothiazolyl, 2-, 3- or4-pyridyl, 2-, 4-, 5- or 6-pyrimidinyl, furthermore preferably1,2,3-triazol-1-, -4- or -5-yl, 1,2,4-triazol-1-, -3- or -5-yl, 1-or5-tetrazolyl, 1,2,3-oxadiazol-4- or -5-yl, 1,2,4-oxadiazol-3- or -5-yl,1,3,4-thiadiazol-2- or -5-yl, 1,2,4-thiadiazol-3- or -5-yl,1,2,3-thiadiazol-4- or -5-yl, 3- or 4-pyridazinyl, pyrazinyl, 1-, 2-,3-, 4-, 5-, 6- or 7-indolyl, 4- or 5-isoindolyl, 1-, 2-, 4- or5-benzimidazolyl, 1-, 2-, 3-, 4-, 5-, 6- or 7-indazolyl, 1-, 3-, 4-, 5-,6- or 7-benzopyrazolyl, 2-, 4-, 5-, 6- or 7-benzoxazolyl, 3-, 4-, 5-, 6-or 7-benzisoxazolyl, 2-, 4-, 5-, 6- or 7-benzothiazolyl, 2-, 4-, 5-, 6-or 7-benzisothiazolyl, 4-, 5-, 6- or 7-benz-2,1,3-oxadiazolyl, 2-, 3-,4-, 5-, 6-, 7- or 8-quinolyl, 1-, 3-, 4-, 5-, 6-, 7- or 8-isoquinolyl,3-, 4-, 5-, 6-, 7- or 8-cinnolinyl, 2-, 4-, 5-, 6-, 7- or8-quinazolinyl, 5- or 6-quinoxalinyl, 2-, 3-, 5-, 6-, 7- or8-2H-benzo-1,4-oxazinyl, further preferably 1,3-benzodioxol-5-yl,1,4-benzodioxan-6-yl, 2,1,3-benzothiadiazol-4- or -5-yl or2,1,3-benzoxadiazol-5-yl.

The heterocyclic radicals may also be partially or fully hydrogenated.Het can thus also denote, for example, 2,3-dihydro-2-, -3-, -4- or-5-furyl, 2,5-dihydro-2-, -3-, -4- or -5-furyl, tetrahydro-2- or-3-furyl, 1,3-dioxolan-4-yl, tetrahydro-2- or -3-thienyl,2,3-dihydro-1-, -2-, -3-, -4- or -5-pyrrolyl, 2,5-dihydro-1-, -2-, -3-,-4- or -5-pyrrolyl, 1-, 2- or 3-pyrrolidinyl, tetrahydro-1-, -2- or-4-imidazolyl, 2,3-dihydro-1-, -2-, -3-, -4- or -5-pyrazolyl,tetrahydro-1-, -3- or -4-pyrazolyl, 1,4-dihydro-1-2-, -3- or -4-pyridyl,1,2,3,4-tetrahydro-1-, -2-, -3-, -4-, -5- or -6-pyridyl, 1-, 2-, 3- or4-piperidinyl, 2-, 3- or 4-morpholinyl, tetrahydro-2-, -3- or-4-pyranyl, 1,4-dioxanyl, 1,3-dioxan-2-, -4- or -5-yl, hexahydro-1-, -3-or -4-pyridazinyl, hexahydro-1-, -2-, -4- or -5-pyrimidinyl, 1-, 2- or3-piperazinyl, 1,2,3,4-tetrahydro-1-, -2-, -3-, -4-, -5-, -6-, -7- or-8-quinolyl, 1,2,3,4-tetrahydro-1-, -2-, -3-, -4-, -5-, -6-, -7- or-8-isoquinolyl, 2-, 3-, 5-, 6-, 7- or8-3,4-dihydro-2H-benzo-1,4-oxazinyl, further preferably2,3-methylenedioxyphenyl, 3,4-methylenedioxyphenyl,2,3-ethylenedioxyphenyl, 3,4-ethylenedioxyphenyl,3,4-(difluoromethylenedioxy)phenyl, 2,3-dihydrobenzofuran-5- or -6-yl,2,3-(2-oxomethylenedioxy)phenyl or also3,4-dihydro-2H-1,5-benzodioxepin-6- or -7-yl, furthermore preferably2,3-dihydrobenzofuranyl or 2,3-dihydro-2-oxofuranyl.

Het preferably denotes a monocyclic saturated, unsaturated or aromaticheterocycle having 1 to 2 N and/or O atoms, which may be unsubstitutedor mono-, di- or trisubstituted by A, Hal, OH and/or OA.

Het particularly preferably denotes a monocyclic saturated heterocyclehaving 1 to 2 N and/or O atoms, which may be unsubstituted or mono- ordisubstituted by A.

In a further embodiment, Het very particularly preferably denotespyrrolidinyl, piperidinyl, morpholinyl or piperazinyl.

In a further embodiment, Het particularly preferably denotes furyl,thienyl, pyrrolyl, imidazolyl, pyridyl, pyrimidinyl, pyrazolyl,thiazolyl, indolyl, pyrrolidinyl, piperidinyl, morpholinyl orpiperazinyl, each of which is unsubstituted or mono-, di- ortrisubstituted by A, Hal, OH and/or OA.

The compounds of the formula I may have one or more chiral centres andcan therefore occur in various stereoisomeric forms. The formula Iencompasses all these forms.

Accordingly, the invention relates, in particular, to the compounds ofthe formula I in which at least one of the said radicals has one of thepreferred meanings indicated above. Some preferred groups of compoundsmay be expressed by the following sub-formulae Ia to Io, which conformto the formula I and in which the radicals not designated in greaterdetail have the meaning indicated for the formula I, but in which

-   in Ia R¹ denotes H or CHO,    -   R² denotes H;-   in Ib R³, R⁴, R⁵, R⁶, R⁷,    -   R⁸, R⁹, R¹⁰, R¹¹ each, independently of one another, denote H,        A, Hal, OR¹² or O—[C(R¹²)₂]_(n)Ar;-   in Ic R⁶ denotes OH;-   in Id R³ denotes H, A or Hal;-   in Ie R⁸ denotes OH, A, phenoxy or Hal;-   in If R⁴, R⁵, R⁷, R⁹, R¹⁰, R¹¹ denote H or A;-   in Ig R⁷, R¹⁰, R¹¹ each, independently of one another, denote H or    Hal;-   in Ih Ar denotes phenyl which is unsubstituted or mono-, di- or    trisubstituted by Hal and/or A;-   in Ii Ar denotes phenyl;-   in Ij Het denotes a monocyclic saturated, unsaturated or aromatic    heterocycle having 1 to 2 N and/or O atoms, which may be    unsubstituted or mono-, di- or trisubstituted by A, Hal, OH and/or    OA;-   in Ik Het denotes a monocyclic saturated heterocycle having 1 to 2 N    and/or O atoms, which may be unsubstituted or mono- or disubstituted    by A;-   in Il Het denotes furyl, thienyl, pyrrolyl, imidazolyl, pyridyl,    pyrimidinyl, pyrazolyl, thiazolyl, indolyl, pyrrolidinyl,    piperidinyl, morpholinyl or piperazinyl, each of which is    unsubstituted or mono-, di- or trisubstituted by A, Hal, OH and/or    OA;-   in Im R¹ denotes H or CHO,    -   R² denotes H,    -   R³, R⁴, R⁵, R⁶, R⁷    -   R⁸, R⁹, R¹⁰, R¹¹ each, independently of one another, denote H,        A, Hal, OR¹² or O—[C(R¹²)₂]_(n)Ar;-   in In R¹ denotes H or CHO,    -   R² denotes H,    -   R³ denotes H, A or Hal,    -   R⁴R⁵R⁷, R⁹, R¹⁰R¹¹ denote H or A,    -   R⁶ denotes OH,    -   R⁸ denotes OH, A, phenoxy or Hal;-   in Io R¹ denotes H, CHO or acetyl,    -   R² denotes H,    -   R³ denotes H, A or Hal,    -   R⁴R⁵R⁷    -   R¹⁰, R¹¹ each, independently of one another, denote H, A or Hal,    -   R⁶ denotes OH,    -   R⁸ denotes OH, A, phenoxy or Hal,    -   R⁹ denotes H, Hal or OA,    -   R⁸ and R⁹ together also denote methylenedioxy;        and pharmaceutically usable derivatives, solvates, salts and        stereoisomers thereof, including mixtures thereof in all ratios.

Particular preference is given to the compounds of the formula Iselected from the group

No. Structural formula “A15”

N′-[2-Hydroxy-2-(3-hydroxyphenyl)acetyl]-2-chloro-4,6-dihydroxybenzohydrazide “A16”

N′-[2-Hydroxy-2-(3-hydroxyphenyl)acetyl]-2-methyl-4,6-dihydroxybenzohydrazide “A17”

N′-[2-Hydroxy-2-(3-hydroxyphenyl)acetyl]-2-ethyl-4,6-dihydroxybenzohydrazide

The compounds according to the invention and also the starting materialsfor their preparation are, in addition, prepared by methods known perse, as described in the literature (for example in the standard works,such as Houben-Weyl, Methoden der organischen Chemie [Methods of OrganicChemistry], Georg-Thieme-Verlag, Stuttgart), to be precise underreaction conditions which are known and suitable for the said reactions.Use may also be made here of variants known per se which are notmentioned here in greater detail.

If desired, the starting materials can also be formed in situ by notisolating them from the reaction mixture, but instead immediatelyconverting them further into the compounds according to the invention.

The starting compounds are generally known. If they are novel, however,they can be prepared by methods known per se.

Compounds of the formula I can preferably be obtained by reacting ahydrazide of the formula II with a compound of the formula III.

The reaction is carried out by methods which are known to the personskilled in the art. The reaction is generally carried out in an inertsolvent, optionally in the presence of an acid-binding agent, preferablyan organic base, such as DIPEA, triethylamine, dimethylaniline, pyridineor quinoline, or an excess of the carboxyl component of the formula Ill.

Examples of suitable inert solvents are hydrocarbons, such as hexane,petroleum ether, benzene, toluene or xylene; chlorinated hydrocarbons,such as trichloroethylene, 1,2-dichloroethane, carbon tetrachloride,chloroform or dichloromethane; alcohols, such as methanol, ethanol,isopropanol, n-propanol, n-butanol or tert-butanol; ethers, such asdiethyl ether, diisopropyl ether, tetrahydrofuran (THF) or dioxane;glycol ethers, such as ethylene glycol monomethyl or monoethyl ether,ethylene glycol dimethyl ether (diglyme); ketones, such as acetone orbutanone; amides, such as acetamide, dimethylacetamide ordimethylformamide (DMF); nitriles, such as acetonitrile; sulfoxides,such as dimethyl sulfoxide (DMSO); carbon disulfide; carboxylic acids,such as formic acid or acetic acid; nitro compounds, such asnitromethane or nitrobenzene; esters, such as ethyl acetate, or mixturesof the said solvents.

Particularly preferred solvents are water or DMF.

The addition of an alkali-metal or alkaline-earth metal hydroxide,carbonate or bicarbonate or another salt of a weak acid of the alkalimetals or alkaline-earth metals, preferably of potassium, sodium,calcium or caesium, may also be favourable.

Depending on the conditions used, the reaction time is between a fewminutes and 14 days, the reaction temperature is between about −30° and140°, normally between −10° and 90°, in particular between about 0° andabout 70°.

In the compounds of the formula III, L preferably denotes Cl, Br, I or afree or reactively modified OH group, such as, for example, an activatedester, an imidazolide or alkylsulfonyloxy having 1-6 C atoms (preferablymethylsulfonyloxy or trifluoromethylsulfonyloxy) or arylsulfonyloxyhaving 6-10 C atoms (preferably phenyl- or p-tolylsulfonyloxy).

Radicals of this type for activation of the carboxyl group in typicalacylation reactions are described in the literature (for example in thestandard works, such as Houben-Weyl, Methoden der organischen Chemie[Methods of Organic Chemistry], Georg-Thieme-Verlag, Stuttgart).

Activated esters are advantageously formed in situ, for example byaddition of HOBt or N-hydroxysuccinimide.

Compounds of the formula I can furthermore preferably be obtained byreacting a hydrazide of the formula IV with a compound of the formula V.

The reaction is generally carried out in an inert solvent, in thepresence of an acid-binding agent, preferably an organic base, such asDIPEA, triethylamine, dimethylaniline, pyridine or quinoline, or anexcess of the carboxyl component of the formula V.

Examples of suitable inert solvents are hydrocarbons, such as hexane,petroleum ether, benzene, toluene or xylene; chlorinated hydrocarbons,such as trichloroethylene, 1,2-dichloroethane, carbon tetrachloride,chloroform or dichloromethane; alcohols, such as methanol, ethanol,isopropanol, n-propanol, n-butanol or tert-butanol; ethers, such asdiethyl ether, diisopropyl ether, tetrahydrofuran (THF) or dioxane;glycol ethers, such as ethylene glycol monomethyl or monoethyl ether,ethylene glycol dimethyl ether (diglyme); ketones, such as acetone orbutanone; amides, such as acetamide, dimethylacetamide ordimethylformamide (DMF); nitriles, such as acetonitrile; sulfoxides,such as dimethyl sulfoxide (DMSO); carbon disulfide; carboxylic acids,such as formic acid or acetic acid; nitro compounds, such asnitromethane or nitrobenzene; esters, such as ethyl acetate, or mixturesof the said solvents.

The addition of an alkali-metal or alkaline-earth metal hydroxide,carbonate or bicarbonate or another salt of a weak acid of the alkalimetals or alkaline-earth metals, preferably of potassium, sodium,calcium or caesium, may also be favourable.

Depending on the conditions used, the reaction time is between a fewminutes and 14 days, the reaction temperature is between about −30° and140°, normally between −10° and 90°, in particular between about 0° andabout 70°.

In the compounds of the formula V, L preferably denotes Cl, Br, I or afree or reactively modified OH group, such as, for example, an activatedester, an imidazolide or alkylsulfonyloxy having 1-6 C atoms (preferablymethylsulfonyloxy or trifluoromethylsulfonyloxy) or arylsulfonyloxyhaving 6-10 C atoms (preferably phenyl- or p-tolylsulfonyloxy).

Radicals of this type for activation of the carboxyl group in typicalacylation reactions are described in the literature (for example in thestandard works, such as Houben-Weyl, Methoden der organischen Chemie[Methods of Organic Chemistry], Georg-Thieme-Verlag, Stuttgart).

Activated esters are advantageously formed in situ, for example byaddition of HOBt or N-hydroxysuccinimide.

Compounds of the formula I can furthermore be obtained by converting aradical R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰ and/or R¹¹ into anotherradical R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰ and/or R¹¹ by, forexample, cleaving an ether by hydrolysis or hydrogenolysis.

The cleavage of an ether is carried out by methods as are known to theperson skilled in the art.

A standard method of ether cleavage, for example of a methyl ether, isthe use of boron tribromide.

Hydrogenolytically removable groups, for example the cleavage of abenzyl ether, can be cleaved off, for example, by treatment withhydrogen in the presence of a catalyst (for example a noble-metalcatalyst, such as palladium, advantageously on a support, such ascarbon). Suitable solvents here are those indicated above, inparticular, for example, alcohols, such as methanol or ethanol, oramides, such as DMF. The hydrogenolysis is generally carried out attemperatures between about 0 and 1000 and pressures between about 1 and200 bar, preferably at 20-300 and 1-10 bar.

Esters can be saponified, for example, using acetic acid or using NaOHor KOH in water, water/THF or water/dioxane, at temperatures between 0and 1000.

Pharmaceutical Salts and Other Forms

The said compounds according to the invention can be used in their finalnon-salt form. On the other hand, the present invention also encompassesthe use of these compounds in the form of their pharmaceuticallyacceptable salts, which can be derived from various organic andinorganic acids and bases by procedures known in the art.Pharmaceutically acceptable salt forms of the compounds of the formula Iare for the most part prepared by conventional methods. If the compoundof the formula I contains a carboxyl group, one of its suitable saltscan be formed by reacting the compound with a suitable base to give thecorresponding base-addition salt. Such bases are, for example, alkalimetal hydroxides, including potassium hydroxide, sodium hydroxide andlithium hydroxide; alkaline-earth metal hydroxides, such as bariumhydroxide and calcium hydroxide; alkali metal alkoxides, for examplepotassium ethoxide and sodium propoxide; and various organic bases, suchas piperidine, diethanolamine and N-methylglutamine. The aluminium saltsof the compounds of the formula I are likewise included. In the case ofcertain compounds of the formula I, acid-addition salts can be formed bytreating these compounds with pharmaceutically acceptable organic andinorganic acids, for example hydrogen halides, such as hydrogenchloride, hydrogen bromide or hydrogen iodide, other mineral acids andcorresponding salts thereof, such as sulfate, nitrate or phosphate andthe like, and alkyl- and monoarylsulfonates, such as ethanesulfonate,toluenesulfonate and benzenesulfonate, and other organic acids andcorresponding salts thereof, such as acetate, trifluoroacetate,tartrate, maleate, succinate, citrate, benzoate, salicylate, ascorbateand the like. Accordingly, pharmaceutically acceptable acid-additionsalts of the compounds of the formula I include the following: acetate,adipate, alginate, arginate, aspartate, benzoate, benzenesulfonate(besylate), bisulfate, bisulfite, bromide, butyrate, camphorate,camphorsulfonate, caprylate, chloride, chlorobenzoate, citrate,cyclopentanepropionate, digluconate, dihydrogenphosphate,dinitrobenzoate, dodecylsulfate, ethanesulfonate, fumarate, galacterate(from mucic acid), galacturonate, glucoheptanoate, gluconate, glutamate,glycerophosphate, hemisuccinate, hemisulfate, heptanoate, hexanoate,hippurate, hydrochloride, hydrobromide, hydroiodide,2-hydroxyethanesulfonate, iodide, isethionate, isobutyrate, lactate,lactobionate, malate, maleate, malonate, mandelate, metaphosphate,methanesulfonate, methylbenzoate, monohydrogenphosphate,2-naphthalenesulfonate, nicotinate, nitrate, oxalate, oleate, palmoate,pectinate, persulfate, phenylacetate, 3-phenylpropionate, phosphate,phosphonate, phthalate, but this does not represent a restriction.

Furthermore, the base salts of the compounds according to the inventioninclude aluminium, ammonium, calcium, copper, iron(III), iron(II),lithium, magnesium, manganese(III), manganese(II), potassium, sodium andzinc salts, but this is not intended to represent a restriction. Of theabove-mentioned salts, preference is given to ammonium; the alkali metalsalts sodium and potassium, and the alkaline-earth metal salts calciumand magnesium. Salts of the compounds of the formula I which are derivedfrom pharmaceutically acceptable organic non-toxic bases include saltsof primary, secondary and tertiary amines, substituted amines, alsoincluding naturally occurring substituted amines, cyclic amines, andbasic ion exchanger resins, for example arginine, betaine, caffeine,chloroprocaine, choline, N,N′-dibenzylethylenediamine (benzathine),dicyclohexylamine, diethanolamine, diethylamine, 2-diethylaminoethanol,2-dimethylaminoethanol, ethanolamine, ethylenediamine,N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine,hydrabamine, isopropylamine, lidocaine, lysine, meglumine,N-methyl-D-glucamine, morpholine, piperazine, piperidine, polyamineresins, procaine, purines, theobromine, triethanolamine, triethylamine,trimethylamine, tripropylamine and tris(hydroxymethyl)methylamine(tromethamine), but this is not intended to represent a restriction.

Compounds of the present invention which contain basicnitrogen-containing groups can be quaternised using agents such as(C₁-C₄)alkyl halides, for example methyl, ethyl, isopropyl andtert-butyl chloride, bromide and iodide; di(C₁-C₄)alkyl sulfates, forexample dimethyl, diethyl and diamyl sulfate; (C₁₀-C₁₈)alkyl halides,for example decyl, dodecyl, lauryl, myristyl and stearyl chloride,bromide and iodide; and aryl(C₁-C₄)alkyl halides, for example benzylchloride and phenethyl bromide. Both water- and oil-soluble compoundsaccording to the invention can be prepared using such salts.

The above-mentioned pharmaceutical salts which are preferred includeacetate, trifluoroacetate, besylate, citrate, fumarate, gluconate,hemisuccinate, hippurate, hydrochloride, hydrobromide, isethionate,mandelate, meglumine, nitrate, oleate, phosphonate, pivalate, sodiumphosphate, stearate, sulfate, sulfosalicylate, tartrate, thiomalate,tosylate and tromethamine, but this is not intended to represent arestriction.

The acid-addition salts of basic compounds of the formula I are preparedby bringing the free base form into contact with a sufficient amount ofthe desired acid, causing the formation of the salt in a conventionalmanner. The free base can be regenerated by bringing the salt form intocontact with a base and isolating the free base in a conventionalmanner. The free base forms differ in a certain respect from thecorresponding salt forms thereof with respect to certain physicalproperties, such as solubility in polar solvents; for the purposes ofthe invention, however, the salts otherwise correspond to the respectivefree base forms thereof.

As mentioned, the pharmaceutically acceptable base-addition salts of thecompounds of the formula I are formed with metals or amines, such asalkali metals and alkaline-earth metals or organic amines. Preferredmetals are sodium, potassium, magnesium and calcium. Preferred organicamines are N,N′-dibenzylethylenediamine, chloroprocaine, choline,diethanolamine, ethylenediamine, N-methyl-D-glucamine and procaine.

The base-addition salts of acidic compounds according to the inventionare prepared by bringing the free acid form into contact with asufficient amount of the desired base, causing the formation of the saltin a conventional manner. The free acid can be regenerated by bringingthe salt form into contact with an acid and isolating the free acid in aconventional manner. The free acid forms differ in a certain respectfrom the corresponding salt forms thereof with respect to certainphysical properties, such as solubility in polar solvents; for thepurposes of the invention, however, the salts otherwise correspond tothe respective free acid forms thereof.

If a compound according to the invention contains more than one groupwhich is capable of forming pharmaceutically acceptable salts of thistype, the invention also encompasses multiple salts. Typical multiplesalt forms include, for example, bitartrate, diacetate, difumarate,dimeglumine, diphosphate, disodium and trihydrochloride, but this is notintended to represent a restriction.

With regard to that stated above, it can be seen that the expression“pharmaceutically acceptable salt” in the present connection is taken tomean an active ingredient which comprises a compound of the formula I inthe form of one of its salts, in particular if this salt form impartsimproved pharmacokinetic properties on the active ingredient comparedwith the free form of the active ingredient or any other salt form ofthe active ingredient used earlier. The pharmaceutically acceptable saltform of the active ingredient can also provide this active ingredientfor the first time with a desired pharmacokinetic property which it didnot have earlier and can even have a positive influence on thepharmacodynamics of this active ingredient with respect to itstherapeutic efficacy in the body.

Compounds of the formula I according to the invention may be chiralowing to their molecular structure and may accordingly occur in variousenantiomeric forms. They can therefore exist in racemic or in opticallyactive form.

Since the pharmaceutical activity of the racemates or stereoisomers ofthe compounds according to the invention may differ, it may be desirableto use the enantiomers. In these cases, the end product or even theintermediates can be separated into enantiomeric compounds by chemicalor physical measures known to the person skilled in the art or evenemployed as such in the synthesis.

In the case of racemic amines, diastereomers are formed from the mixtureby reaction with an optically active resolving agent. Examples ofsuitable resolving agents are optically active acids, such as the R andS forms of tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid,mandelic acid, malic acid, lactic acid, suitably N-protected amino acids(for example N-benzoylproline or N-benzenesulfonylproline), or thevarious optically active camphorsulfonic acids. Also advantageous ischromatographic enantiomer resolution with the aid of an opticallyactive resolving agent (for example dinitrobenzoylphenylglycine,cellulose triacetate or other derivatives of carbohydrates or chirallyderivatised methacrylate polymers immobilised on silica gel). Suitableeluents for this purpose are aqueous or alcoholic solvent mixtures, suchas, for example, hexane/isopropanol/acetonitrile, for example in theratio 82:15:3.

The invention furthermore relates to the use of the compounds and/orphysiologically acceptable salts thereof for the preparation of amedicament (pharmaceutical composition), in particular by non-chemicalmethods. They can be converted into a suitable dosage form here togetherwith at least one solid, liquid and/or semi-liquid excipient or adjuvantand, if desired, in combination with one or more further activeingredients.

The invention furthermore relates to medicaments comprising at least onecompound according to the invention and/or pharmaceutically usablederivatives, solvates and stereoisomers thereof, including mixturesthereof in all ratios, and optionally excipients and/or adjuvants.

Pharmaceutical formulations can be administered in the form of dosageunits which comprise a predetermined amount of active ingredient perdosage unit. Such a unit can comprise, for example, 0.5 mg to 1 g,preferably 1 mg to 700 mg, particularly preferably 5 mg to 100 mg, of acompound according to the invention, depending on the condition treated,the method of administration and the age, weight and condition of thepatient, or pharmaceutical formulations can be administered in the formof dosage units which comprise a predetermined amount of activeingredient per dosage unit. Preferred dosage unit formulations are thosewhich comprise a daily dose or part-dose, as indicated above, or acorresponding fraction thereof of an active ingredient. Furthermore,pharmaceutical formulations of this type can be prepared using a processwhich is generally known in the pharmaceutical art.

Pharmaceutical formulations can be adapted for administration via anydesired suitable method, for example by oral (including buccal orsublingual), rectal, nasal, topical (including buccal, sublingual ortransdermal), vaginal or parenteral (including subcutaneous,intramuscular, intravenous or intradermal) methods. Such formulationscan be prepared using all processes known in the pharmaceutical art by,for example, combining the active ingredient with the excipient(s) oradjuvant(s).

Pharmaceutical formulations adapted for oral administration can beadministered as separate units, such as, for example, capsules ortablets; powders or granules; solutions or suspensions in aqueous ornon-aqueous liquids; edible foams or foam foods; or oil-in-water liquidemulsions or water-in-oil liquid emulsions.

Thus, for example, in the case of oral administration in the form of atablet or capsule, the active-ingredient component can be combined withan oral, non-toxic and pharmaceutically acceptable inert excipient, suchas, for example, ethanol, glycerol, water and the like. Powders areprepared by comminuting the compound to a suitable fine size and mixingit with a pharmaceutical excipient comminuted in a similar manner, suchas, for example, an edible carbohydrate, such as, for example, starch ormannitol. A flavour, preservative, dispersant and dye may likewise bepresent.

Capsules are produced by preparing a powder mixture as described aboveand filling shaped gelatine shells therewith. Glidants and lubricants,such as, for example, highly disperse silicic acid, talc, magnesiumstearate, calcium stearate or polyethylene glycol in solid form, can beadded to the powder mixture before the filling operation. A disintegrantor solubiliser, such as, for example, agar-agar, calcium carbonate orsodium carbonate, may likewise be added in order to improve theavailability of the medicament after the capsule has been taken.

In addition, if desired or necessary, suitable binders, lubricants anddisintegrants as well as dyes can likewise be incorporated into themixture. Suitable binders include starch, gelatine, natural sugars, suchas, for example, glucose or beta-lactose, sweeteners made from maize,natural and synthetic rubber, such as, for example, acacia, tragacanthor sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes,and the like. The lubricants used in these dosage forms include sodiumoleate, sodium stearate, magnesium stearate, sodium benzoate, sodiumacetate, sodium chloride and the like. The disintegrants include,without being restricted thereto, starch, methylcellulose, agar,bentonite, xanthan gum and the like. The tablets are formulated by, forexample, preparing a powder mixture, granulating or dry-pressing themixture, adding a lubricant and a disintegrant and pressing the entiremixture to give tablets. A powder mixture is prepared by mixing thecompound comminuted in a suitable manner with a diluent or a base, asdescribed above, and optionally with a binder, such as, for example,carboxymethylcellulose, an alginate, gelatine or polyvinylpyrrolidone, adissolution retardant, such as, for example, paraffin, an absorptionaccelerator, such as, for example, a quaternary salt, and/or anabsorbent, such as, for example, bentonite, kaolin or dicalciumphosphate. The powder mixture can be granulated by wetting it with abinder, such as, for example, syrup, starch paste, acadia mucilage orsolutions of cellulose or polymer materials and pressing it through asieve. As an alternative to granulation, the powder mixture can be runthrough a tableting machine, giving lumps of non-uniform shape which arebroken up to form granules. The granules can be lubricated by additionof stearic acid, a stearate salt, talc or mineral oil in order toprevent sticking to the tablet casting moulds. The lubricated mixture isthen pressed to give tablets. The compounds according to the inventioncan also be combined with a free-flowing inert excipient and thenpressed directly to give tablets without carrying out the granulation ordry-pressing steps. A transparent or opaque protective layer consistingof a shellac sealing layer, a layer of sugar or polymer material and agloss layer of wax may be present. Dyes can be added to these coatingsin order to be able to differentiate between different dosage units.

Oral liquids, such as, for example, solution, syrups and elixirs, can beprepared in the form of dosage units so that a given quantity comprisesa prespecified amount of the compound. Syrups can be prepared bydissolving the compound in an aqueous solution with a suitable flavour,while elixirs are prepared using a non-toxic alcoholic vehicle.Suspensions can be formulated by dispersion of the compound in anon-toxic vehicle. Solubilisers and emulsifiers, such as, for example,ethoxylated isostearyl alcohols and polyoxyethylene sorbitol ethers,preservatives, flavour additives, such as, for example, peppermint oilor natural sweeteners or saccharin, or other artificial sweeteners andthe like, can likewise be added.

The dosage unit formulations for oral administration can, if desired, beencapsulated in microcapsules. The formulation can also be prepared insuch a way that the release is extended or retarded, such as, forexample, by coating or embedding of particulate material in polymers,wax and the like.

The compounds according to the invention and salts, solvates andphysiologically functional derivatives thereof can also be administeredin the form of liposome delivery systems, such as, for example, smallunilamellar vesicles, large unilamellar vesicles and multilamellarvesicles. Liposomes can be formed from various phospholipids, such as,for example, cholesterol, stearylamine or phosphatidylcholines.

The compounds according to the invention and the salts, solvates andphysiologically functional derivatives thereof can also be deliveredusing monoclonal antibodies as individual carriers to which the compoundmolecules are coupled. The compounds can also be coupled to solublepolymers as targeted medicament carriers. Such polymers may encompasspolyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamidophenol, polyhydroxyethylaspartamidophenol or polyethylene oxidepolylysine, substituted by palmitoyl radicals. The compounds mayfurthermore be coupled to a class of biodegradable polymers which aresuitable for achieving controlled release of a medicament, for examplepolylactic acid, poly-epsilon-caprolactone, polyhydroxybutyric acid,polyorthoesters, polyacetals, polydihydroxypyrans, polycyanoacrylatesand crosslinked or amphipathic block copolymers of hydrogels.

Pharmaceutical formulations adapted for transdermal administration canbe administered as independent plasters for extended, close contact withthe epidermis of the recipient. Thus, for example, the active ingredientcan be delivered from the plaster by iontophoresis, as described ingeneral terms in Pharmaceutical Research, 3(6), 318 (1986).

Pharmaceutical compounds adapted for topical administration can beformulated as ointments, creams, suspensions, lotions, powders,solutions, pastes, gels, sprays, aerosols or oils.

For the treatment of the eye or other external tissue, for example mouthand skin, the formulations are preferably applied as topical ointment orcream. In the case of formulation to give an ointment, the activeingredient can be employed either with a paraffinic or a water-misciblecream base. Alternatively, the active ingredient can be formulated togive a cream with an oil-in-water cream base or a water-in-oil base.

Pharmaceutical formulations adapted for topical application to the eyeinclude eye drops, in which the active ingredient is dissolved orsuspended in a suitable carrier, in particular an aqueous solvent.

Pharmaceutical formulations adapted for topical application in the mouthencompass lozenges, pastilles and mouthwashes.

Pharmaceutical formulations adapted for rectal administration can beadministered in the form of suppositories or enemas.

Pharmaceutical formulations adapted for nasal administration in whichthe carrier substance is a solid comprise a coarse powder having aparticle size, for example, in the range 20-500 microns, which isadministered in the manner in which snuff is taken, i.e. by rapidinhalation via the nasal passages from a container containing the powderheld close to the nose. Suitable formulations for administration asnasal spray or nose drops with a liquid as carrier substance encompassactive-ingredient solutions in water or oil.

Pharmaceutical formulations adapted for administration by inhalationencompass finely particulate dusts or mists, which can be generated byvarious types of pressurised dispensers with aerosols, nebulisers orinsufflators.

Pharmaceutical formulations adapted for vaginal administration can beadministered as pessaries, tampons, creams, gels, pastes, foams or sprayformulations.

Pharmaceutical formulations adapted for parenteral administrationinclude aqueous and non-aqueous sterile injection solutions comprisingantioxidants, buffers, bacteriostatics and solutes, by means of whichthe formulation is rendered isotonic with the blood of the recipient tobe treated; and aqueous and non-aqueous sterile suspensions, which maycomprise suspension media and thickeners. The formulations can beadministered in single-dose or multidose containers, for example sealedampoules and vials, and stored in freeze-dried (lyophilised) state, sothat only the addition of the sterile carrier liquid, for example waterfor injection purposes, immediately before use is necessary.

Injection solutions and suspensions prepared in accordance with therecipe can be prepared from sterile powders, granules and tablets.

It goes without saying that, in addition to the above particularlymentioned constituents, the formulations may also comprise other agentsusual in the art with respect to the particular type of formulation;thus, for example, formulations which are suitable for oraladministration may comprise flavours.

A therapeutically effective amount of a compound of the presentinvention depends on a number of factors, including, for example, theage and weight of the human or animal, the precise condition whichrequires treatment, and its severity, the nature of the formulation andthe method of administration, and is ultimately determined by thetreating doctor or vet. However, an effective amount of a compoundaccording to the invention for the treatment is generally in the rangefrom 0.1 to 100 mg/kg of body weight of the recipient (mammal) per dayand particularly typically in the range from 1 to 10 mg/kg of bodyweight per day. Thus, the actual amount per day for an adult mammalweighing 70 kg is usually between 70 and 700 mg, where this amount canbe administered as an individual dose per day or more usually in aseries of part-doses (such as, for example, two, three, four, five orsix) per day, so that the total daily dose is the same. An effectiveamount of a salt or solvate or of a physiologically functionalderivative thereof can be determined as the fraction of the effectiveamount of the compound according to the invention per se. It can beassumed that similar doses are suitable for the treatment of otherconditions mentioned above.

The invention furthermore relates to medicaments comprising at least onecompound according to the invention and/or pharmaceutically usablederivatives, solvates and stereoisomers thereof, including mixturesthereof in all ratios, and at least one further medicament activeingredient.

The invention also relates to a set (kit) consisting of separate packsof

-   (a) an effective amount of a compound according to the invention    and/or pharmaceutically usable derivatives, solvates and    stereoisomers thereof, including mixtures thereof in all ratios, and-   (b) an effective amount of a further medicament active ingredient.

The set comprises suitable containers, such as boxes, individualbottles, bags or ampoules. The set may, for example, comprise separateampoules, each containing an effective amount of a compound according tothe invention and/or pharmaceutically usable derivatives, solvates andstereoisomers thereof, including mixtures thereof in all ratios, and aneffective amount of a further medicament active ingredient in dissolvedor lyophilised form.

Use

The present compounds are suitable as pharmaceutical active ingredientsfor mammals, in particular for humans, in the treatment of SGK-induceddiseases.

The invention thus relates to the use of compounds according to claim 1,and pharmaceutically usable derivatives, solvates and stereoisomersthereof, including mixtures thereof in all ratios, for the preparationof a medicament for the treatment of diseases in which the inhibition,regulation and/or modulation of kinase signal transduction plays a role.Prefernce is given here to SGK.

Preference is given to the use of compounds according to claim 1, andpharmaceutically usable derivatives, solvates and stereoisomers thereof,including mixtures thereof in all ratios, for the preparation of amedicament for the treatment of diseases which are influenced byinhibition of SGKs by the compounds according to claim 1.

The present invention encompasses the use of the compounds according toclaim 1 according to the invention and/or physiologically acceptablesalts and solvates thereof for the preparation of a medicament for thetreatment or prevention of diabetes (for example diabetes mellitus,diabetic nephropathy, diabetic neuropathy, diabetic angiopathy andmicroangiopathy), obesity, metabolic syndrome (dyslipidaemia), systemicand pulmonary hypertonia, cardiovascular diseases (for example cardiacfibroses after myocardial infarction, cardiac hypertrophy and cardiacinsufficiency, arteriosclerosis) and kidney diseases (for exampleglomerulosclerosis, nephrosclerosis, nephritis, nephropathy, electrolyteexcretion disorder), generally in fibroses and inflammatory processes ofany type (for example liver cirrhosis, pulmonary fibrosis, fibrosingpancreatitis, rheumatism and arthroses, Crohn's disease, chronicbronchitis, radiation fibrosis, sclerodermatitis, cystic fibrosis,scarring, Alzheimer's disease).

The compounds according to the invention can also inhibit the growth ofcancer, tumour cells and tumour metastases and are therefore suitablefor tumour therapy.

The compounds according to the invention are furthermore used for thetreatment of coagulopathies, such as, for example, dysfibrinogenaemia,hypoproconvertinaemia, haemophilia B, Stuart-Prower defect, prothrombincomplex deficiency, consumption coagulopathy, hyperfibrinolysis,immunocoagulopathy or complex coagulopathies, and also in neuronalexcitability, for example epilepsy. The compounds according to theinvention can also be employed therapeutically in the treatment ofglaucoma or a cataract. The compounds according to the invention arefurthermore used in the treatment of bacterial infections and inantiinfection therapy. The compounds according to the invention can alsobe employed therapeutically for increasing learning ability andattention.

Preference is given to the use of compounds according to claim 1, andpharmaceutically usable derivatives, solvates and stereoisomers thereof,including mixtures thereof in all ratios, for the preparation of amedicament for the treatment or prevention of diabetes, obesity,metabolic syndrome (dyslipidaemia), systemic and pulmonary hypertonia,cardiovascular diseases and kidney diseases, generally in fibroses andinflammatory processes of any type, cancer, tumour cells, tumourmetastases, coagulopathies, neuronal excitability, glaucoma, cataract,bacterial infections and in anti-infection therapy, for increasinglearning ability and attention, and for the treatment and prophylaxis ofcell ageing and stress.

Diabetes is preferably diabetes mellitus, diabetic nephropathy, diabeticneuropathy, diabetic angiopathy and microangiopathy.

Cardiovascular diseases are preferably cardiac fibroses after myocardialinfarction, cardiac hypertrophy, cardiac insufficiency andarteriosclerosis.

Kidney diseases are preferably glomerulosclerosis, nephrosclerosis,nephritis, nephropathy and electrolyte excretion disorder.

Fibroses and inflammatory processes are preferably liver cirrhosis,pulmonary fibrosis, fibrosing pancreatitis, rheumatism and arthroses,Crohn's disease, chronic bronchitis, radiation fibrosis,sclerodermatitis, cystic fibrosis, scarring, Alzheimer's disease.

Assays

The compounds according to the invention described in the examples weretested in the assays described below and were found to havekinaseinhibitory activity. Further assays are known from the literatureand could easily be performed by the person skilled in the art (see, forexample, Dhanabal et al., Cancer Res. 59:189-197; Xin et al., J. Biol.Chem. 274:9116-9121; Sheu et al., Anticancer Res. 18:4435-4441; Ausprunket al., Dev. Biol. 38:237-248; Gimbrone et al., J. Natl. Cancer Inst.52:413-427; Nicosia et al., In Vitro 18:538-549).

The inhibition of SGK1 protein kinase can be determined in the filterbinding method.

Above and below, all temperatures are indicated in OC. In the followingexamples, “conventional work-up” means: if necessary, water is added,the pH is adjusted, if necessary, to values between 2 and 10, dependingon the constitution of the end product, the mixture is extracted withethyl acetate or dichloromethane, the phases are separated, the organicphase is dried over sodium sulfate and evaporated, and the product ispurified by chromatography on silica gel and/or by crystallisation. Rfvalues on silica gel; eluent: ethyl acetate/methanol 9:1.

Mass spectrometry (MS): EI (electron impact ionisation) M⁺

-   -   FAB (fast atom bombardment) (M+H)⁺    -   ESI (electrospray ionisation) (M+H)⁺(unless indicated otherwise)

EXAMPLE 1

The preparation ofN′-[2-(3,4-difluorophenyl)-2-hydroxyacetyl]-2,4-dihydroxy-6-methylbenzohydrazide(“A1”) is carried out analogously to the following scheme:

N₂H₅OH is monoacylated using 2,4-dibenzyloxy-6-methylbenzoic acid.Yield: 2,4-dibenzyloxy-6-methylbenzohydrazide (63%); m.p. 136-1370.

2,4-Dibenzyloxy-6-methylbenzohydrazide is hydrogenated. Yield:2,4-dihydroxy-6-methylbenzohydrazide (89%); m.p. 2260 (decomposition).

1.3 282 mg of 3,4-difluoromandelic acid, 410 mg of2,4-dihydroxy-6-methylbenzohydrazide, 431 mg of1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (WSCD) and 164 mg of1-hydroxybenzotriazole (HOBt) are stirred in 1.5 ml of DMF for 3 h. Themixture is subjected to conventional work-up and chromatographed onsilica gel. The uniform fractions are combined, evaporated andrecrystallised from EtOAc/petroleum ether. Yield 250 mg of “A1” (46%),m.p. 220° C.

The following compounds are obtained analogously:

Structural formula No. Name m.p. [° C.] “A2”

N′-[2-hydroxy-2-(3-phenoxyphenyl)acetyl]-2,4-dihydroxy-6-methylbenzohydrazide 177-178 “A3”

N′-(2-hydroxy-2-phenylacetyl)-2,4-dihydroxy-6- methylbenzohydrazide188-189 “A4”

N′-[2-hydroxy-2-(3-chlorophenyl)acetyl]-2,4-dihydroxy-6-methylbenzohydrazide 215 “A5”

N′-[2-hydroxy-2-(3-trifluoromethylphenyl)acetyl]-2,4-dihydroxy-6-methylbenzohydrazide 226 “A6”

N′-[2-acetoxy-2-(3-chlorophenyl)acetyl]-2,4-dihydroxy-6-methylbenzohydrazide  98-100 “A7”

N′-[2-hydroxy-2-(3-fluorophenyl)acetyl]-2,4-dihydroxy-6-methylbenzohydrazide 215-216 “A8”

N′-[2-hydroxy-2-(3,5-difluorophenyl)acetyl]-2,4-dihydroxy-6-methylbenzohydrazide 215-217 “A9”

N′-[2-hydroxy-2-(2,3,4,5,6-pentafluorophenyl)-acetyl]-2,4-dihydroxy-6-methylbenzohydrazide 224-225 “A10”

N′-(2-benzo-1,3-dioxol-5-yl-2-hydroxyacetyl)-2,4-dihydroxy-6-methylbenzohydrazide 215-216 “A11”

N′-[2-hydroxy-2-(3-hydroxy-4-methoxyphenyl)-acetyl]-2,4-dihydroxy-6-methylbenzohydrazide 126-128 “A12”

N′-[2-hydroxy-2-(3-chlorophenyl)acetyl]-2,4-dihydroxy-5-chlorobenzohydrazide 221-222 “A13”

N′-[2-hydroxy-2-(3-chlorophenyl)acetyl]-3-chloro-2-ethyl-4-hydroxybenzohydrazide 164-165 “A14”

N′-[(R)-2-(3-chlorophenyl)-2-hydroxyacetyl]-2,4-dihydroxy-6-methylbenzohydrazide 234-235 “A19”

N′[2-hydroxy-2-(3-methylphenyl)acetyl]-2,4-dihydroxy-6-methylbenzohydrazide 222-223 “A20”

N′-[2-hydroxy-2-(3,4-difluorophenyl)acetyl]-2,4-dihydroxy-5-methylbenzohydrazide 202-203 “A21”

N′-[2-formyloxy-2-(3,4-difluorophenyl)acetyl]-2,4-dihydroxy-6-methylbenzohydrazide 92-93 (decomposition) “A22”

N′-[2-hydroxy-2-(3,4-difluorophenyl)acetyl]-2,4-dihydroxy-6-ethylbenzohydrazide 189-191 “A23”

N′-[2-hydroxy-2-(3,4-difluorophenyl)acetyl]-4-hydroxy-2-ethyl-3-methylbenzohydrazide 191

EXAMPLE 2 Preparation ofN′-[2-hydroxy-2-(3-hydroxyphenyl)acetyl]-2-chloro-4,6-dihydroxybenzohydrazide(“A15”)

720 mg ofN′-[2-hydroxy-2-(3-hydroxyphenyl)acetyl]-2-chloro-4,6-dibenzyloxybenzohydrazidein 20 ml of THF+0.2 ml of 32% HCl are hydrogenated with the calculatedamount of H₂ using 360 mg of Pd/C. The hydrogenation solution isevaporated and chromatographed on silica gel. The uniform fractions arecombined, evaporated and recrystallised from EtOAc. Yield 310 mg (65%)of “A15”, m.p. 230-231°.

The following compounds are obtained analogously:

m.p. No. Structural formula [° C.] “A16”

N′-[2-hydroxy-2-(3-hydroxyphenyl)acetyl]-2-methyl-4,6-dihydroxybenzohydrazide 214-215 “A17”

N′-[2-hydroxy-2-(3-hydroxyphenyl)acetyl]-2-ethyl-4,6-dihydroxybenzohydrazide 233-234

EXAMPLE 3 Preparation ofN′-(2-hydroxy-2-phenylacetyl)-2-methyl-4,6-dihydroxybenzohydrazide(“A18”)

1.6 g of 2,4-dihydroxy-6-methylbenzoic acid are refluxed with 4 ml ofSOCl₂ until a clear solution forms. The SOCl₂ is stripped off,subsequently evaporated to dryness a further 2× with CH₂Cl₂. The acidchloride is then dissolved in 3 ml of DMF, and 1.14 g of mandelichydrazide are added. After the mixture has been stirred at roomtemperature for 2 hours, it is added to H₂O, extracted with EtOAc, driedand evaporated to a small volume. Yield 1.49 g (50%) of “A18”, m.p.188-189°.

Alternative Preparation EXAMPLE 4

1.82 g of 2,4-dihydroxy-6-methylbenzohydrazide are dissolved in 10 ml ofDMF. 1.71 g of mandeloyl chloride are slowly added. After the mixturehas been stirred at room temperature for 2 hours, it is added to H₂O,extracted with EtOAc, dried and evaporated to a small volume. Yield 2.16g (68%) of “A18”, m.p. 188-189°.

Syntheses of Precursors EXAMPLE 5N′-[2-hydroxy-2-(3-hydroxyphenyl)acetyl]-2,4-dibenzyloxy-6-methylbenzohydrazide

The substance is prepared analogously to Example 1 from2,4-dibenzyloxy-6-methylbenzohydrazide and 3-hydroxymandelic acid in ayield of 47%, m.p. 181-1820 (from Me₂COH/Et₂O).

The following compounds are obtained analogously:

N′-[2-hydroxy-2-(3-hydroxyphenyl)acetyl]-2-chloro-4,6-dibenzyloxybenzohydrazide,m.p. 160-162° (from Me₂COH/Et₂O), 61% yield andN′-[2-hydroxy-2-(3-hydroxyphenyl)acetyl]-2,4-dibenzyloxy-6-ethylbenzohydrazide,m.p. 205-2060 (from Me₂COH/Et₂O), 90% yield.

EXAMPLE 6 2,4-Bisbenzyloxy-6-ethylbenzaldehyde

1.9 g of dihydroxy-6-ethylbenzaldehyde, 3.48 ml of benzyl chloride and4.7 g of K₂CO₃ are stirred in 5.2 ml of DMF at 90° for 2 h. The batch isdiluted with EtOAc and washed with water. The organic phase is driedusing Na₂SO₄, evaporated and chromatographed on silica gel. The uniformfractions are combined and evaporated. The oily residue solidifies onstanding after a few days. Treatment with ether/petroleum ether 1:1gives 3.5 g (88%) of 2,4-bisbenzyloxy-6-ethylbenzaldehyde, whichdiscolours in air.

3-Chloro-2-ethyl-4-hydroxybenzoic acid is benzylated analogously:3-chloro-2-ethyl-4-benzyloxybenzoic acid is obtained in a yield of 78%,m.p. 208-210°.

EXAMPLE 7 2,4-Bisbenzyloxy-6-ethylbenzoic acid

3.3 g of 2,4-bisbenzyloxy-6-ethylbenzaldehyde are dissolved in 63 ml ofDMSO. A solution of 7.9 g of NaClO₂ and 7.9 g of NaHCO₃ in 32 ml ofwater is added slowly with ice-cooling, during which the temperaturedoes not exceed 40° C. The mixture is stirred for a further 2 h, beforebeing diluted with further water and extracted 2× with EtOAc. Thecombined organic phases are washed with water, dried using Na₂SO₄,evaporated, chromatographed on silica gel and crystallised from Me₂COH:yield 2.21 g (64%) of 2,4-bisbenzyloxy-6-ethylbenzoic acid, m.p.126-1270.

The following are prepared analogously:

2,4-bisbenzyloxy-6-chlorobenzoic acid, m.p. 135-1360 (35%) and3-chloro-2-ethyl-4-hydroxybenzoic acid from3-chloro-2-ethyl-4-hydroxybenzaldehyde: yield 51%, m.p. 138-1390.

EXAMPLE 8 2,4-Dibenzyloxy-6-ethylbenzohydrazide

The substance is prepared by the method indicated in Example 1 from2,4-bisbenzyloxy-6-ethylbenzoic acid and hydrazinium hydroxide: yield75%, m.p. 140-141°.

An analogous preparation procedure also gives2,4-dibenzyloxy-6-chlorobenzohydrazide: yield 61%, m.p. 166-1670, and4-benzyloxy-3-chloro-2-ethylbenzohydrazide: yield 85%, m.p. 182-1840.

EXAMPLE 9 2,4-Bisbenzyloxy-6-chlorobenzaldehyde

12 g of chloro-3,5-dibenzyloxybenzene are dissolved in 40 ml of DMF. 12ml of POCl₃ are slowly added dropwise at 5-10°. The mixture is allowedto react further for 90 min at room temperature, then overnight at 80°C. The solution is evaporated in a Rotavapor, then added to 200 ml oficewater. The mixture is extracted 3× with EtOAc, washed with water,dried and evaporated. Silica gel chromatography gives 8.2 g (63%) of2,4-bisbenzyloxy-6-chlorobenzaldehyde, which crystallises from (Me₂C)₂O,m.p. 85-86°.

EXAMPLE 10 Acetoxy(3-chlorophenyl)acetic acid

1 g of racemic 3-chloromandelic acid is mixed with 2 ml of acetylchloride.

A clear solution forms, which, after 2 h, is evaporated in a Rotavaporand crystallised using (Me₂C)₂O/petroleum ether. Yield 670 mg (55%),m.p. 118°.

EXAMPLE 11 3-Chloro-2-ethyl-4-hydroxybenzohydrazide

The compound is prepared by hydrogenation of 300 mg of3-chloro-2-ethyl-4-benzyloxybenzohydrazide in 10 ml of MeOH and 145 μlof 32% HCl on Pd/Cu. Yield 165 mg (78%), 233-2350 (EtOAc/MeCN).

The following is prepared analogously:5-chloro-2,4-dihydroxybenzohydrazide, yield 84%, m.p. 260°.

EXAMPLE 12 3-Chloro-2-ethyl-4-hydroxybenzaldehyde

3.4 g of N-chlorosuccinimide in 40 ml of CHCl₃ are added dropwise over aperiod of 45 min to 4 g of 2-ethyl-4-hydroxybenzaldehyde, dissolved in80 ml of CHCl₃ and 1.5 ml of conc. HCl. The mixture is stirred for afurther 1 h, washed with water, dried and evaporated.

Silica-gel chromatography gives 1 g (20%) of3-chloro-2-ethyl-4-hydroxybenzaldehyde (m.p. 850, polar substance onsilica gel with ether/petroleum ether 1:1) in addition to5-chloro-2-ethyl-4-hydroxybenzaldehyde (m.p. 830, moderate polarity) and3,5-dichloro-2-ethyl-4-hydroxybenzaldehyde (m.p. 117-118°, nonpolar).

The following examples relate to pharmaceutical compositions:

EXAMPLE A Injection Vials

A solution of 100 g of an active ingredient according to the inventionand 5 g of disodium hydrogenphosphate in 3 l of bidistilled water isadjusted to pH 6.5 using 2 N hydrochloric acid, sterile filtered,transferred into injection vials, lyophilised under sterile conditionsand sealed under sterile conditions. Each injection vial contains 5 mgof active ingredient.

EXAMPLE B Suppositories

A mixture of 20 g of an active ingredient according to the inventionwith 100 g of soya lecithin and 1400 g of cocoa butter is melted, pouredinto moulds and allowed to cool. Each suppository contains 20 mg ofactive ingredient.

EXAMPLE C Solution

A solution is prepared from 1 g of an active ingredient according to theinvention, 9.38 g of NaH₂PO₄.2H₂O, 28.48 g of Na₂HPO₄.12H₂O and 0.1 g ofbenzalkonium chloride in 940 ml of bidistilled water. The pH is adjustedto 6.8, and the solution is made up to 1 l and sterilised byirradiation. This solution can be used in the form of eye drops.

EXAMPLE D Ointment

500 mg of an active ingredient according to the invention are mixed with99.5 g of Vaseline under aseptic conditions.

EXAMPLE E Tablets

A mixture of 1 kg of active ingredient, 4 kg of lactose, 1.2 kg ofpotato starch, 0.2 kg of talc and 0.1 kg of magnesium stearate ispressed to give tablets in a conventional manner in such a way that eachtablet contains 10 mg of active ingredient.

EXAMPLE F Dragees

Tablets are pressed analogously to Example E and subsequently coated ina conventional manner with a coating of sucrose, potato starch, talc,tragacanth and dye.

EXAMPLE G Capsules

2 kg of active ingredient are introduced into hard gelatine capsules ina conventional manner in such a way that each capsule contains 20 mg ofthe active ingredient.

EXAMPLE H Ampoules

A solution of 1 kg of an active ingredient according to the invention in60 l of bidistilled water is sterile filtered, transferred intoampoules, lyophilised under sterile conditions and sealed under sterileconditions. Each ampoule contains 10 mg of active ingredient.

1. Compounds of the formula I

in which R¹, R² each, independently of one another, denote H, CHO oracetyl, R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹ each, independently of oneanother, denote H, A, OSO₂A, Hal, NO₂, OR¹², N(R¹²)₂, CN, O—COA,—[C(R¹²)₂]_(n)COOR¹², O—[C(R¹²)₂]_(n)COOR¹², SO₃H, —[C(R¹²)₂]_(n)Ar,—CO—Ar, O—[C(R²)₂]_(n)Ar, —[C(R¹²)₂]_(n)Het, —[C(R¹²)₂]_(n)C≡CH,O—[C(R¹²)₂]_(n)C—CH, —[C(R¹²)₂]_(n)CON(R¹²)₂,—[C(R¹²)₂]_(n)CONR¹²N(R¹²)₂, O—[C(R¹²)₂]_(n)CON(R¹²)₂,O—[C(R²)₂]_(n)CONR²N(R²)₂, NR¹²COA, NR¹²CON(R¹²)₂, NR¹²SO₂A, N(SO₂A)₂,COR¹², S(O)_(m)Ar, SO₂NR² or S(O)_(m)A, R³ and R⁴ together also denoteCH═CH—CH═CH, R³ and R⁴, R⁷ and R⁸ or R⁸ and R⁹ together also denotealkylene having 3, 4 or 5 C atoms, in which one or two CH₂ groups may bereplaced by oxygen, A denotes unbranched or branched alkyl having 1-6 Catoms, in which 1-7H atoms may be replaced by F, or cyclic alkyl having3-7 C atoms, Ar denotes phenyl, naphthyl or biphenyl, each of which isunsubstituted or mono-, di- or trisubstituted by Hal, A, OR¹², N(R¹²)₂,NO₂, CN, phenyl, CON(R¹²)₂, NR¹²COA, NR¹²CON(R¹²)₂, NR¹²SO₂A, COR¹²,SO₂N(R¹²)₂, S(O)_(m)A, —[C(R¹²)₂]_(n)—COOR¹² and/or—O[C(R¹²)₂]_(n)—COOR¹², Het denotes a mono- or bicyclic saturated,unsaturated or aromatic heterocycle having 1 to 4 N, O and/or S atoms,which may be mono-, di- or trisubstituted by Hal, A, OR¹², N(R¹²)₂, NO₂,CN, COOR¹²CON(R¹²)₂, NR¹²COA, NR¹²SO₂A, COR¹², SO₂NR¹², S(O)_(m)A, ═S,═NR¹² and/or ═O (carbonyl oxygen), R¹² denotes H or A, Hal denotes F,Cl, Br or I, m denotes 0, 1 or 2, n denotes 0, 1, 2 or 3, o denotes 1, 2or 3, and pharmaceutically usable derivatives, salts, solvates andstereoisomers thereof, including mixtures thereof in all ratios. 2.Compounds according to claim 1 in which R¹ denotes H or CHO, R² denotesH, and pharmaceutically usable derivatives, salts, solvates andstereoisomers thereof, including mixtures thereof in all ratios. 3.Compounds according to claim 1 in which R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰,R¹¹ each, independently of one another, denote H, A, Hal, OR¹² orO—[C(R¹²)₂]_(n)Ar, and pharmaceutically usable derivatives, salts,solvates and stereoisomers thereof, including mixtures thereof in allratios.
 4. Compounds according to claim 1 in which R⁶ denotes OH, andpharmaceutically usable derivatives, salts, solvates and stereoisomersthereof, including mixtures thereof in all ratios.
 5. Compoundsaccording to claim 1 in which R³ denotes H, A or Hal, andpharmaceutically usable derivatives, salts, solvates and stereoisomersthereof, including mixtures thereof in all ratios.
 6. Compoundsaccording to claim 1 in which R⁸ denotes OH, A, phenoxy or Hal, andpharmaceutically usable derivatives, salts, solvates and stereoisomersthereof, including mixtures thereof in all ratios.
 7. Compoundsaccording to claim 1 in which R⁴, R⁵, R⁶, R⁷, R⁹, R¹⁰, R¹¹, denote H orA, and pharmaceutically usable derivatives, salts, solvates andstereoisomers thereof, including mixtures thereof in all ratios. 8.Compounds according to claim 1 in which R⁷, R¹⁰, R¹¹ each, independentlyof one another, denote H or Hal, and pharmaceutically usablederivatives, salts, solvates and stereoisomers thereof, includingmixtures thereof in all ratios.
 9. Compounds according to claim 1 inwhich Ar denotes phenyl which is unsubstituted or mono-, di- ortrisubstituted by Hal and/or A, and pharmaceutically usable derivatives,salts, solvates and stereoisomers thereof, including mixtures thereof inall ratios.
 10. Compounds according to claim 1 in which Ar denotesphenyl, and pharmaceutically usable derivatives, salts, solvates andstereoisomers thereof, including mixtures thereof in all ratios. 11.Compounds according to claim 1 in which Het denotes a monocyclicsaturated, unsaturated or aromatic heterocycle having 1 to 2 N and/or Oatoms, which may be unsubstituted or mono-, di- or trisubstituted by A,Hal, OH and/or OA, and pharmaceutically usable derivatives, salts,solvates and stereoisomers thereof, including mixtures thereof in allratios.
 12. Compounds according to claim 1 in which Het denotes amonocyclic saturated heterocycle having 1 to 2 N and/or O atoms, whichmay be unsubstituted or mono- or disubstituted by A, andpharmaceutically usable derivatives, salts, solvates and stereoisomersthereof, including mixtures thereof in all ratios.
 13. Compoundsaccording to claim 1 in which Het denotes furyl, thienyl, pyrrolyl,imidazolyl, pyridyl, pyrimidinyl, pyrazolyl, thiazolyl, indolyl,pyrrolidinyl, piperidinyl, morpholinyl or piperazinyl, each of which isunsubstituted or mono-, di- or trisubstituted by A, Hal, OH and/or OA,and pharmaceutically usable derivatives, salts, solvates andstereoisomers thereof, including mixtures thereof in all ratios. 14.Compounds according to claim 1 in which R¹ denotes H or CHO, R² denotesH, R³, R⁴, R⁵, R⁶R⁷, R⁸, R⁹, R¹⁰, R¹¹ each, independently of oneanother, denote H, A, Hal, OR¹² or O—[C(R²)₂]_(n)Ar, andpharmaceutically usable derivatives, salts, solvates and stereoisomersthereof, including mixtures thereof in all ratios.
 15. Compoundsaccording to claim 1 in which R¹ denotes H or CHO, R² denotes H, R³denotes H, A or Hal, R⁴, R⁵, R⁷, R⁹, R¹⁰, R¹¹ denote H or A, R⁶ denotesOH, R⁸ denotes OH, A, phenoxy or Hal, and pharmaceutically usablederivatives, salts, solvates and stereoisomers thereof, includingmixtures thereof in all ratios.
 16. Compounds according to claim 1 inwhich R¹ denotes H or CHO, R² denotes H, R³ denotes H, A or Hal, R⁴, R⁵,R⁷, R⁹, R¹⁰, R¹¹ denote H, A or Hal, R⁸ and R⁹ together also denotemethylenedioxy, R⁶ denotes OH, R⁸ denotes OH, A, phenoxy or Hal, andpharmaceutically usable derivatives, salts, solvates and stereoisomersthereof, including mixtures thereof in all ratios.
 17. Compoundsaccording to claim 1 in which R¹ denotes H, CHO or acetyl, R² denotes H,R³ denotes H, A or Hal, R⁴, R⁵, R⁷, R¹⁰, R¹¹ each, independently of oneanother, denote H, A or Hal, R⁶ denotes OH, R⁸ denotes OH, A, phenoxy orHal, R⁹ denotes H, Hal or OA, R⁸ and R⁹ together also denotemethylenedioxy, and pharmaceutically usable derivatives, salts, solvatesand stereoisomers thereof, including mixtures thereof in all ratios. 18.Compounds according to claim 1 selected from the group Structuralformula No. Name “A1”

N′-[2-(3,4-Difluorophenyl)-2-hydroxyacetyl]-2,4-dihydroxy-6-methylbenzohydrazide “A2”

N′-[2-Hydroxy-2-(3-phenoxyphenyl)acetyl]-2,4-dihydroxy-6-methylbenzohydrazide “A3”

N′-(2-Hydroxy-2-phenylacetyl)-2,4-dihydroxy-6-methyl- benzohydrazide“A4”

N′-[2-Hydroxy-2-(3-chlorophenyl)acetyl]-2,4-dihydroxy-6-methylbenzohydrazide “A5”

N′-[2-Hydroxy-2-(3-trifluoromethylphenyl)acetyl]-2,4-dihydroxy-6-methylbenzohydrazide “A6”

N′-[2-Acetoxy-2-(3-chlorophenyl)acetyl]-2,4-dihydroxy-6-methylbenzohydrazide “A7”

N′-[2-Hydroxy-2-(3-fluorophenyl)acetyl]-2,4-dihydroxy-6-methylbenzohydrazide “A8”

N′-[2-Hydroxy-2-(3,5-difluorophenyl)acetyl]-2,4-dihydroxy-6-methylbenzohydrazide “A9”

N′-[2-Hydroxy-2-(2,3,4,5,6-pentafluorophenyl)acetyl]-2,4-dihydroxy-6-methylbenzohydrazide “A10”

N′-(2-Benzo-1,3-dioxol-2-hydroxyacetyl)-2,4-dihydroxy-6-methylbenzohydrazide “A11”

N′-[2-hydroxy-2-(3-hydroxy-4-methoxyphenyl)acetyl]-2,4-dihydroxy-6-methylbenzohydrazide “A12”

N′-[2-Hydroxy-2-(3-chlorophenyl)acetyl]-2,4-dihydroxy-5-chlorobenzohydrazide “A13”

N′-[2-Hydroxy-2-(3-chlorophenyl)acetyl]-3-chloro-2-ethyl-4-hydroxybenzohydrazide “A14”

N′-[(R)-2-(3-Chlorophenyl)-2-hydroxyacetyl]-2,4-dihydroxy-6-methylbenzohydrazide “A15”

N′-[2-Hydroxy-2-(3-hydroxyphenyl)acetyl]-2-chloro-4,6-dihydroxybenzohydrazide “A16”

N′-[2-Hydroxy-2-(3-hydroxyphenyl)acetyl]-2-methyl-4,6-dihydroxybenzohydrazide “A17”

N′-[2-Hydroxy-2-(3-hydroxyphenyl)acetyl]-2-ethyl-4,6-dihydroxybenzohydrazide “A18”

N′-(2-Hydroxy-2-phenylacetyl)-2-methyl-4,6-dihydroxy- benzohydrazide“A19”

N′-[2-Hydroxy-2-(3-methylphenyl)acetyl]-2,4-dihydroxy-6-methylbenzohydrazide “A20”

N′-[2-Hydroxy-2-(3,4-difluorophenyl)acetyl]-2,4-dihydroxy-5-methylbenzohydrazide “A21”

N′-[2-Formyloxy-2-(3,4-difluorophenyl)acetyl]-2,4-dihydroxy-6-methylbenzohydrazide “A22”

N′[2-Hydroxy-2-(3,4-difluorophenyl)acetyl]-2,4-dihydroxy-6-ethylbenzohydrazide “A23”

N′-[2-Hydroxy-2-(3,4-difluorophenyl)acetyl]-4-hydroxy-2-ethyl-3-methylbenzohydrazide

and pharmaceutically usable derivatives, salts, solvates andstereoisomers thereof, including mixtures thereof in all ratios. 19.Process for the preparation of compounds of the formula I according toclaim 1 and pharmaceutically usable derivatives, solvates, salts andstereoisomers thereof, characterised in that a) a compound of theformula II

in which R¹, R⁷, R⁸, R⁹, R¹⁰ and R¹¹ have the meanings indicated inclaim 1, is reacted with a compound of the formula III

in which L denotes Cl, Br, I or a free or reactively functionallymodified OH group, and R², R¹, R⁴, R¹ and R⁶ have the meanings indicatedin claim 1, or b) a compound of the formula IV

in which R², R³, R⁴, R⁵ and R⁶ have the meanings indicated in claim 1,is reacted with a compound of the formula V

in which L denotes Cl, Br, I or a free or reactively functionallymodified OH group, and R¹, R⁷, R⁸, R⁹, R¹⁰ and R¹¹ have the meaningsindicated in claim 1, or c) a radical R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸,R⁹, R¹⁰ and/or R¹¹ in a compound of the formula I is converted intoanother radical R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰ and/or R¹¹ bycleaving an ether by hydrolysis or hydrogenolysis, and/or a base or acidof the formula I is converted into one of its salts.
 20. Medicamentscomprising at least one compound according to claim 1 and/orpharmaceutically usable derivatives, solvates and stereoisomers thereof,including mixtures thereof in all ratios, and optionally excipientsand/or adjuvants.
 21. A method of using compounds of the formula Iaccording to claim 1, and pharmaceutically usable derivatives, solvatesand stereoisomers thereof, including mixtures thereof in all ratios,comprising preparing a medicament with the compounds of formula I forthe treatment or prophylaxis of diseases in which the inhibition,regulation and/or modulation of kinase signal transduction plays a role.22. A method according to claim 21, where the kinase is SGK.
 23. Amethod according to claim 22 wherein the medicament is for the treatmentof diseases which are influenced by inhibition of SGKs by saidcompounds.
 24. A method according to claim 23 wherein the medicament isfor the treatment or prevention of diabetes, obesity, metabolic syndrome(dyslipidaemia), systemic and pulmonary hypertonia, cardiovasculardiseases and kidney diseases, generally in fibroses and inflammatoryprocesses of any type, cancer, tumour cells, tumour metastases,coagulopathies, neuronal excitability, glaucoma, cataract, bacterialinfections and in antiinfection therapy, for increasing learning abilityand attention, and for the treatment and prophylaxis of cell ageing andstress, and for the treatment of tinnitus.
 25. A method according toclaim 24, where diabetes is diabetes mellitus, diabetic nephropathy,diabetic neuropathy, diabetic angiopathy or microangiopathy.
 26. Amethod according to claim 25, where cardiovascular diseases are cardiacfibroses after myocardial infarction, cardiac hypertrophy, cardiacinsufficiency or arteriosclerosis.
 27. A method according to claim 24,where fibroses and inflammatory processes are liver cirrhosis, pulmonaryfibrosis, fibrosing pancreatitis, rheumatism and arthroses, Crohn'sdisease, chronic bronchitis, radiation fibrosis, sclerodermatitis,cystic fibrosis, scarring or Alzheimer's disease.
 29. Medicamentscomprising at least one compound according to claim 1 and/orpharmaceutically usable derivatives, solvates and stereoisomers thereof,including mixtures thereof in all ratios, and at least one furthermedicament active ingredient.
 30. Set (kit) consisting of separate packsof (a) an effective amount of a compound according to claim 1 and/orpharmaceutically usable derivatives, solvates and stereoisomers thereof,including mixtures thereof in all ratios, and (b) an effective amount ofa further medicament active ingredient.